A wide variety of diseases and other conditions which afflict humans are caused by deficiencies in certain enzymes in certain tissues.
Illustratively, Gaucher disease is associated with glucocerebrosidase deficiency and results in brain and bone marrow abnormalities. Hurler's syndrome and Scheie syndrome are associated with α-iduronidase deficiency; the former results in bone, cartilage, and brain abnormalities, while the latter results in corneal clouding and deformed hands. Canavan's disease is associated with aspartoacylase deficiency and results in brain and muscle abnormalities. Fabry disease is associated with α-galactosidase deficiency and results in renal, cardiac, and cerebrovascular abnormalities. Niemann-Pick disease is associated with sphingomyelinase deficiency and results in liver, spleen, lymph node, and bone marrow abnormalities with cerebral involvement in late stage. Schindler disease is associated with α-N-acetylgalactosaminadase deficiency and results in brain abnormalities. Sanfillippo A syndrome is associated with sulfamidase deficiency and results in severe mental retardation and mild skeletal abnormalities. Morquio A and Morquio B syndrome syndromes are, respectively, associated (i) with galactose-4-sulfatase, galactose-6-sulfatase, galactosamine-4-sulfatase, and/or galactosamine-6-sulfatase deficiency and (ii) with β-galactosidase deficiency, and each results in skeletal abnormalities. Pompe disease is associated with α-glucosidase deficiency and results in muscle abnormalities, particularly cardiac muscle abnormalities, as well as brain abnormalities.
A variety of methods have been proposed for treating diseases and other conditions involving enzyme deficiency.
For example, one possible way of treating enzyme deficiency conditions is by enzyme replacement therapy, where exogenous enzyme is delivered to the tissue or tissues where deficiency in the enzyme exists. However, currently used enzyme replacement therapy methods have not been successful when treating diseases and other conditions associated with enzyme deficiencies in the brain or in bone. For example, it has been reported that currently used intravenous methods for enzyme delivery for treating Gaucher disease and for treating syndromes associated with α-iduronidase deficiency (e.g., Hurler's syndrome, Scheie syndrome, and Hurler/Scheie syndrome) are not effective for delivering the necessary enzyme to the brain or to bone (Villodie et al., “Management of Neuropathic Gaucher Disease: A European Consensus,” J. Inherit. Metab. Dis., 3:319-327 (2001) and Hermann et al., “Gaucher Disease: An Assessment of Skeletal Involvement and Therapeutic Responses to Enzyme Replacement,” Skeletal Radiol., 26(12):687-696 (1977)).
Another possible way of treating enzyme deficiency diseases is by gene therapy by delivering an exogenous gene encoding the deficient enzyme to the tissues where the enzyme is deficient. Once delivered to the desired tissues, the enzyme is produced in situ by expression of the exogenous gene. However, delivery of exogenous genes to the brain and to bone has proven to be problematic. For example, while expression of exogenous genes in brain has previously been achieved in vivo with either viral vectors or cationic liposomes, delivery of cationic liposomes, viral vectors, genes, and other large biologically active materials to the brain generally requires highly invasive routes of administration.
It is believed that the difficulties encountered in delivering enzymes and genes, as well as other large biologically-active materials, to the brain is the result of the inability of such large biologically-active materials to cross the brain capillary wall which forms the blood-brain barrier (“BBB”). The existence of the BBB frequently necessitates administering the large biologically active materials, such as enzymes and exogenous genes, intracerebrally (e.g., via craniotomy). Intracerebral administration requires specialized skills and renders the brain more susceptible to infection.
For all of the above reasons, a need remains for increasing the permeability of the blood-brain barrier, and a need remains for methods of delivering large biologically active materials, such as enzymes and nucleic acid molecules, to the brain and to bone. The present invention is directed, in part, to addressing these needs.